Histone demethylase KDM2B promotes triple negative breast cancer proliferation by suppressing p15INK4B, p16INK4A, and p57KIP2 transcription

Abstract

H3K4me3 and H3K36me2 histone demethylase KDM2B is an epigenetic regulatory factor involved in cell proliferation in numerous cells including breast cancer cells, however, the regulatory mechanism of KDM2B in cell proliferation of breast cancer cells, specifically in triple negative breast cancer (TNBC), remains largely unknown. In this study, we showed that higher expression level of KDM2B was associated with poor prognosis in TNBC. Using cell proliferation assay, we found that KDM2B promoted TNBC cell proliferation by suppressing the transcription of the cell cycle inhibitors p15^INK4B, p16^INK4A, and p57^KIP2. Chromatin immunoprecipitation assay results showed that KDM2B bound to the promoters of these genes and thereby reduced the H3K4me3 and H3K36me2 levels, leading to the suppression of gene transcription in a histone demethylation activity-dependent manner. Silencing of p15^INK4B, p16^INK4A, and p57^KIP2 in TNBC cells was shown to restore the promoting effect of KDM2B on TNBC cell proliferation. The present study reveals a novel cell regulatory mechanism through which KDM2B promotes TNBC cell proliferation by binding to the promoters of p15^INK4B, p16^INK4A, and p57^KIP2, which reduces H3K4me3 and H3K36me2 levels to suppress gene transcription.

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